Frontotemporal lobar degeneration (FTLD) belongs to a group of clinically, pathologically and genetically heterogeneous disorders associated with atrophy in the frontal lobe and temporal lobe of the brain. It is the second most common cause of early-onset of dementia. Cognitive symptoms are variable and include dementia, changes of the behavior as well as personality, language dysfunctions, and/or psychosis with are due to the degeneration of the frontal and temporal cortex. Due to its symptoms FTLD can be divided into three groups (i) behavioral-variant frontotemporal dementia (bvFTLD), (ii) semantic dementia (SD), or (iii) progressive nonfluent aphasia (PNFA). Patients with FTLD die 5-10 years after symptom onset, since no suitable therapy is available. However, 50% of FTLD patient were shown to have a positive family history and compared to amyotrophic lateral sclerosis (ALS) seems to represent a disease continuum with a shared underlying pathogenesis. Although both autosomal dominant disorders were shown to be genetically and pathologically heterogeneous, see, e.g., Vance et al., Brain 129 (2006), 868-876, genetic analysis identified a heterozygous expanded hexanucleotide repeat (GGGGCC) located between the noncoding exons 1a and 1b of the C9ORF72 gene as the most common genetic cause of FTLD and ALS; see, e.g., DeJesus-Hernandez et al., Neuron 72 (2011), 245-256 and Renton et al., Neuron 72 (2011), 257-268. In particular, it was shown that the unconventional non-ATG translation of the sense transcript in the three alternate reading frames, i.e. of the expanded hexanucleotide repeats, resulted in the production, generation and aggregation of three different polypeptides, each composed of repeating units of two amino acids (dipeptide repeats, DPRs), i.e. poly-(Gly-Ala; GA), poly-(Gly-Pro; GP) and poly-(Gly-Arg; GR). Furthermore, translation of corresponding antisense transcripts results in the generation of poly-(Pro-Arg; PR), poly-(Pro-Ala; PA), and poly-(Gly-Pro; GP). These C9ORF72-dipeptide repeat (DPR) expansions were shown to account for up to 30% of FTLD, 50% of ALS and 80% of FTLD-ALS patients with the highest mutation frequencies observed in US and EU Caucasian populations. Additionally, patients with C9ORF72-DPR expansion with more than 19 repeats had a lower age of onset, increased incidence of neurological disorders, and a propensity towards psychosis or hallucinations compared to patients with other forms of FTLD and/or ALS; see, e.g., Harms et al., Neurobiol. Aging 34 (2013), e13-e19.
However, also other diseases and/or disorders have been reported which seem to be associated with a hexanucleotide repeat expansions, e.g., spinocerebellar ataxia type 36. Indeed, such tandem repeats (either as microsatellites or minisatellites) are mutation-prone DNA in both eukaryotic and prokaryotic organisms. For example, the cell surface adhesins of bacteria often contain the minisatellite SD repeats, encoding the amino acid pair of serine-aspartate with an array of 18-nucleotide repeats, whose elements follow the consensus GAYTCNGAYTCN GAYAGY, where N is any base and Y is T or C, especially in Staphylococcal strains. It has been found that serine-aspartate repeats (SDR) are present in a variable repetitive region of these adhesins, such as the R domain of clumping factor A (C1fA); see, e.g., Hazenbos et al., PLOS Pathogens 9 (2013), e1003653.
Treatments for diseases and/or disorders associated with a dipeptide repeat (DPR) expansion, e.g. medicaments which slow down the progression of the disease, are missing. The major focus of medical care so far lies in the provision of pharmaceuticals for the treatment of the often very stressful accompanying symptoms. However, so far there is no evidence for an effective treatment.
This technical problem is solved by the embodiments characterized in the claims and described further below and illustrated in the Examples and Figures.